Nanomedicine-protein interactions: Understanding protein corona composition effects on nanomedicine cellular uptake

从替补席到临床，一种新的候选药物在发展过程中将面临多重障碍和挑战。在肿瘤学药物开发中，必须在实现肿瘤生物利用度和潜在的非靶标器官毒性之间取得平衡-纳米药物已成为克服这些挑战的一种有希望的解决方案。当静脉注射时，纳米药物将暴露在血液中的各种生物分子中。其中一些分子会吸附在纳米药物的表面，形成“日冕”，改变其化学特性和生物命运。疏水性纳米药物具有较短的循环半衰期，这是因为在被单核吞噬系统识别后，更高程度的调理和随后的清除。为了通过减少免疫识别清除来改善循环半衰期，利用亲水性分子(如聚乙二醇酯)进行隐身已成为纳米医学研究的标准方法。本文将研究纳米粒子的物理化学特性如何影响纳米粒子表面的蛋白质电晕形成，以及随后蛋白质电晕形成对纳米医学物理化学特性和细胞相互作用的影响。正交粒子计量学技术将被应用于在血浆和细胞裂解液中进行蛋白质电晕处理之前和之后的纳米医学物理化学特性的表征。到目前为止，有限数量的研究评估了蛋白质电晕形成对纳米医学物理化学特性和随后的生物命运的影响。由于PLGA纳米粒子作为纳米载体进行了广泛的研究，已建立的安全性和临床成熟度，以及严重缺乏关于NP电晕特性的公开报道，因此将被作为模型进行研究。这项工作的发现，与平行的蛋白质组学分析相结合，为开发纳米医学生物命运的预测模型提供了空间。作为纳米粒子物理化学属性的函数，本研究将是一系列研究的第一部分，该系列研究纳米粒子蛋白质在不同时间尺度上的电晕演化的动态和终点表征。了解蛋白质电晕组成已被认为是了解颗粒制造过程、关键质量属性和随后的体内性能之间的相互作用的关键因素。最终，纳米药物生物命运的预测模型将在设计和建造具有可调蛋白质电晕轮廓的新型纳米药物方面产生阶段性变化，可用于改善药物的生物分布和治疗效果。

From bench to clinic, a new drug candidate will face multiple roadblocks and challenges in its development. In oncology drug development, a balance has to be met between achieving tumour bioavailability and potential off-target organ toxicity- Nanomedicines have emerged as a promising solution to overcoming such challenges. When administered intravenously, a nanomedicine will be exposed to various biomolecules in blood. Some of these molecules will adsorb onto the nanomedicine surface, forming a 'corona', altering its chemical identity and biological fate. Hydrophobic nanomedicines have a shorter circulation half-life owing to a higher degree of opsonisation and subsequent clearance following recognition by the mononuclear phagocytic system. In a bid to improve circulation half-lives through reduced immune recognition clearance, stealthing with hydrophilic molecules such as PEG has been implemented as a standard approach in nanomedicine research.This studentship will investigate how nanoparticle physicochemical characteristics impact protein corona formation on nanoparticle surfaces, and the subsequent impact of protein corona formation on nanomedicine physicochemical characteristics and cellular interactions. Orthogonal particle metrology technologies will be applied to the characterization of nanomedicine physicochemical characteristics prior to and following protein corona treatment in plasma and cellular lysate. A limited number of studies to date have evaluated the impact of protein corona formation on nanomedicine physicochemical characteristics and subsequent biological fate. PLGA nanoparticles will be investigated as a model due to their extensive investigation as nanocarriers, established safety profile, maturity in the clinic, and significant lack of published reports on NP corona characterization. Findings from this work, in combination with parallel proteomics analysis offer the scope for developing predictive models of nanomedicine biological fate. This studentship will be the first of a series considering both dynamic and endpoint characterization of nanoparticle protein corona evolution over various timescales as a function of nanoparticle physicochemical attributes. Understanding protein corona composition has been recognized as a critical factor in deconvoluting the interplay between particle manufacture processes, critical quality attributes, and subsequent in vivo performance. Ultimately, predictive models of nanomedicine biological fate will create a step-change in the design and construction of novel nanomedicines with tunable protein corona profiles that can be exploited to improve drug biodistribution and therapeutic efficacy.